Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a secretable multifunctional protein. Since the concept of APE1/Ref-1 secretion was established in 2013, several studies have demonstrated the usefulness of APE1/Ref-1 as a serological biomarker. However, the role of APE1/Ref-1 in atherosclerotic vascular inflammation is unclear. Herein, we investigated the role of APE1/Ref-1 in atherosclerotic apolipoprotein E (ApoE^-/-) mice fed with a Western-type diet as an animal model of vascular inflammation. We found that serologic APE1/Ref-1 was strongly correlated with vascular inflammation in these mice. Neutrophil/lymphocyte ratio, endothelial cell/macrophage activation, and atherosclerotic plaque formation, reflected by atherosclerotic inflammation, were increased in the ApoE^-/- mice fed with a Western-type diet. Correlation analysis showed a high correlation between plasma APE1/Ref-1 levels and neutrophil/lymphocyte ratio, a marker of systemic inflammation. We conclude that APE1/Ref-1 expression is upregulated in aortic endothelial cells/macrophages of atherosclerotic mice, and that plasma APE1/Ref-1 levels could predict atherosclerotic inflammation, it is a useful biomarker for vascular inflammation in atherosclerosis.

Some studies demonstrate that gallic acid (GA) and myricetin (MYR) isolated from Rhus trilobata provide the therapeutic activity of the plant against cancer. However, few reports demonstrate that both compounds also could have therapeutic potential in ovarian cancer treatment. Therefore, to evaluate the cytotoxic activity of GA and MYR against ovarian cancer cells and to determine the possible action mechanism present is important. With this purpose, SKOV-3 ovarian adenocarcinoma cells (HTB-77™, ATCC®) were cultivated at 37°C with 5% CO₂ according to supplier's instructions for determine the biological activity of GA and MYR by confocal/transmission electron microscopy, PI-flow cytometry, H₂DCF-DA, MTT and Annexin V/PI assays. Possible molecular targets of the compounds were determined by Similarity Ensemble Approach model. Results showed that GA and Myr treatments decreased viability of SKOV-3 cells at 50 and 166 μg/mL respectively (p ≤ 0.05, ANOVA vs vehicle group); As well as morphological changed (cytoplasmatic reduction, nuclear chromatin condensation, cytoplasmic vesicles increment, polymerized actin, and stabilized tubulin), cell cycle arrest (GA: 8.3% G₂/M and MYR: 78% G₁), and apoptosis induction (GA: 18.9% and MYR: 8.1%), because to ROS generation (34 to 42%) for 24 h (p ≤ 0.05, ANOVA vs vehicle group). In silico studies demonstrated that GA and MYR interact with carbonic anhydrase and PI3K, respectively. As conclusions, GA and MYR show cytotoxic activity against SKOV-3 cells through ROS production, which modify the cytoskeleton and induce apoptosis mainly. Therefore, GA and Myr could be considered as a starting point for the development of novel anticancer agents.

Improvement of treatment outcomes in patients with locally advanced or metastatic urothelial carcinoma represents an important unmet need, since survival remains poor in patients who progressed after first-line treatment. The purpose of this study was to investigate the effects of ramucirumab, a human monoclonal antibody which binds to VEGFR-2, in the treatment of locally advanced or metastatic urothelial carcinoma. A literature search of PubMed and CENTRAL was conducted. Outcomes of interest were overall survival (OS), progression-free survival (PFS) and rate of adverse events. Time-to-event outcomes were combined using the generic inverse-variance method and presented as hazard ratio (HR) with 95% confidence intervals (95%CI), while dichotomous events were combined using the Mantel-Haenszel method and presented as odds ratio (OR) with 95%CI. All analyses were performed in RevMan 5.3. Literature search identified two randomized controlled trials. Addition of ramucirumab to docetaxel resulted in a statistically significant improvement in PFS (HR=0.55, 95%CI 0.31-0.96, p=0.030), while the difference was not significant for OS (HR=0.86, 95%CI 0.71-1.04, p=0.12). Subgroup analysis by sex, age (<65 and ≥65 years), baseline hemoglobin (<10 g/dL and ≥10 g/dL), presence of visceral metastases and presence of liver metastases did not identify a subgroup in which improvement in OS was present. The difference in treatment-related grade≥3 adverse events was not significant (OR=1.47, 95%CI 0.95-2.27, p=0.08). Ramucirumab in addition to docetaxel significantly improved PFS in patients with locally advanced or metastatic urothelial carcinoma. Future studies are necessary to identify a subset of patients who might have a significant improvement in OS.

Background: Apolipoprotein A1 (APOA1) is a potential biomarker due its variable concentration in different types of cancers.

Objective: We for the first time evaluated the association between APOA1 -75 G/A, +83 C/T genotypes in tandem with APOA1 protein expression in urine samples to find out risk and potential relationship for differentially expressed urinary proteins and APOA1 genotypes.

Design: The study included 108 cases of bladder tumors and 150 healthy controls that were frequency matched to cases with respect to age, sex and smoking status. Genotyping was performed by PCR-RFLP and urinary expression of APOA1 protein was done by ELISA.

Results: Bladder tumor cases were significantly associated with APOA1-75 AA genotype (p<0.05) while as APOA1+83 CT heterozygotes showed association with cases (p<0.05). The overall distribution of different haplotypes showed a marked difference between cases and controls in GT when compared with wild type GC (p<0.03). Bladder tumor cases that carried variant genotype APOA1-75AA presented more (70.0%) with higher expression (≥20ng/ml) of APOA1 urinary protein and differed significantly against wild typeGG (p=0.03). Again, in low grade bladder tumors, urinary APOA1 protein significantly presented more (52.4% vs. 15.4% high grade) with higher expression (≥20ng) while high grade tumor cases (84.6% vs. 47.5% low grade) showed lower APOA1expression (<20ng/ml) (O.R= 6.08, p=0.002).

Conclusions: We found a strong association between APOA1-75G/A and risk for bladder tumor and its relation to urinary protein expression that substantiates its possible role as a marker for risk assessment of the disease and promising diagnostic marker for different grades of malignant bladder tumors

Key Words: Bladder cancer; APOA1; Genotype; Allele; Protein expression; Haplotype

In the process of searching for novel compounds with antipsychotic properties, structure-based virtual screening was conducted [1]. Among found dopamine D₂ receptor antagonists, the compound D2AAK3 with 115 nM affinity for D₂ receptor was identified. It also shows nanomolar or low micromolar affinity for D₁, D₃, 5-HT_1A, 5-HT_2A and 5-HT₇ receptors, what makes it a good candidate for a multi-target drug. Interactions of D2AAK3 with its molecular targets at the molecular level were studied in silico by performing homology modeling, molecular docking and molecular dynamics. The main contact of D2AAK3 with all studied receptors is the electrostatic interaction between the proton attached to the nitrogen atom of the ligand and the conserved Asp(3.32), what is typical for orthosteric binding mode in aminergic GPCRs. Behavioral studies [2] performed for D2AAK3 revealed that it decreases amphetamine-induced hyperactivity measured as spontaneous locomotor activity in mice, improves memory consolidation after acute treatment in passive avoidance test and exhibits anxiogenic activity 30 minutes after acute treatment in mice in elevated plus maze (this effect was reversed 60 minutes after administration of D2AAK3). Further optimization of reported compound, toward obtaining molecule with properties resembling atypical antipsychotics, will be conducted.

References:

1. Kaczor AA, Silva AG, Loza MI, Kolb P, Castro M, Poso A (2016) ChemMedChem 11:718-729.
2. Kaczor AA, Targowska-Duda KM, Budzyńska B, Biała G, Silva AG, Castro M (2016) Neurochemistry International 96:84-99.